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Featured Clinical Topic-Endocrinology: Subcutaneous Administration of Testosterone as an Alternative to Intramuscular Injection

24 Jan 2018 2:58 PM | MSHP Office (Administrator)

Subcutaneous Administration of Testosterone as an Alternative to Intramuscular Injection

Authors: Jackson Warner, PharmD Candidate 2018, UMKC School of Pharmacy
Andrew Bzowyckyj, PharmD, BCPS, CDE: UMKC School of Pharmacy/Truman Medical Center

Introduction
Subcutaneous (SC) testosterone is a novel delivery method that may alleviate concerns associated with intramuscular injections, improving adherence and patient attitude towards therapy. Intramuscular (IM) testosterone injections are often reported to cause pain, bruising, and a need to schedule injections with a healthcare provider if unable to self-administer.1 IM injections often result in supraphysiologic levels of testosterone, followed by subtherapeutic troughs. This fluctuation in hormone levels can lead to an undesirable variability in mood, energy, and libido. Topical formulations can have adverse events such as local reactions, risk of skin-to-skin transmission, unpleasant odors, and unreliable absorption.2 These formulations are not often covered by insurance and may be cost-prohibitive. A form of SC testosterone is currently available as implantable pellets. However, this formulation requires placement by a physician and carries the risk of infection and fibrosis, or extrusion of the pellets.2 Ease of administration, less pain compared to IM injections, and decreased fluctuation of hormone levels are all attractive qualities that may sway patients and providers alike to prefer SC injections of current testosterone formulations.

Pharmacokinetic Profile of SC Testosterone
Several studies have observed the effects of SC administration of testosterone cypionate (TC) and enanthate (TE) on serum levels, alleviation of the hypogonadal symptoms, and masculinization of transgender patients to determine its viability as an alternative to IM injections. Spratt et al.1 measured the testosterone levels in 96 female-to-male (FTM) transgender patients using weekly SC injections. The initial dose was 50mg (TC or TE, based on availability) SC once weekly. Doses were increased sequentially until normal serum total testosterone levels were attained (348-1197ng/dL). All patients (n=63) achieved normal serum total testosterone levels, regardless of BMI, suggesting that obesity is not a limitation of SC testosterone. Average levels were significantly different between the normal weight and obese patients (754 vs. 606 ng/dL, p-0.04), but not overweight patients (765ng/dL). Though not clinically significant, all subjects who received at least six months of optimized therapy experienced satisfactory masculinization. Kaminetsky et al.2 compared TE 50mg SC (n=15) and 100mg SC (n=14) once weekly to TE 200mg IM every two weeks in males with hypogonadism. The 50mg dose provided an increase in total testosterone levels, which fell back to baseline between doses. However, the 100mg dose demonstrated a rise in total testosterone levels for the first three weeks. At week four and beyond, this group demonstrated steady-state exposure. The apparent half-life was 239.63 hours (100 mg SC) and 172.57 hours (200 mg IM). The kinetic profile of SC testosterone appears to be dose-proportional, with AUC and Cmax values for the 100mg SC dose being approximately twice those of the 50mg SC dose. 100mg SC testosterone demonstrated a similar overall AUC compared to 200mg IM testosterone at week five and six, suggesting that bioavailability is similar. McFarland et al.3 observed the total testosterone levels of 11 FTM transgender patients who were already on weekly doses of TC SC with documented therapeutic levels. Levels were taken prior to injection and at serial intervals post-injection (mean dose: 75mg weekly). Serum concentrations significantly increased between pre-injection and six hours post-injection (497 vs. 656 ng/dL; p=0.02), but did not significantly decrease between the sample drawn prior to injection and the sample seven days afterwards (497 vs. 477 ng/dL, p=0.58). The regression analysis of the relationship between SC testosterone dose and serum total testosterone concentration yielded a significant positive correlation (r2=0.59, p=0.006), further demonstrating dose-dependent kinetics. A separate regression model included BMI as a covariate (mean BMI 28.5 ± 7.4, range of 20.3–39.3 kg/m2). In this model, only the dose of testosterone was found to be a significant predictor of the total testosterone level, (standardized β coefficient, 0.77, p=0.005) showing that BMI is likely not a predictor of serum testosterone levels and should not be regarded as a limitation to using SC testosterone. Olson et al.4 measured the total testosterone levels in 35 FTM transgender patients naïve to hormone replacement therapy. TC doses were started at 25mg SC every two weeks and gradually increased to 50mg weekly as tolerated (mean dose: 46.4mg). Thirty-two of the 35 patients achieved testosterone levels within the normal male range at six months. The six-month total testosterone levels significantly increased from baseline levels (521.4 vs 35.2 ng/dL, p<0.001).

Lastly, a pilot study5 investigated the effect of subcutaneous TE in 22 hypogonadal men. The starting doses ranged from 25–50mg SC weekly. One week after initial injection, a trough and peak total testosterone level were taken with doses adjusted based on these levels and patient-reported symptoms (mean dose: 55 mg weekly). The mean trough was 418 ng/dL (normal range 288–1110) and the mean peak was 624 ng/dL. All 22 patients had both peaks and troughs within the normal range.

Safety and Tolerability
SC testosterone is well tolerated and generally safe with injection site reactions being the most commonly reported concern. One case of cellulitis was observed, but resolved without intervention.1 Insomnia (n=2), acne (n=1), and minor pain at the injection site have also been reported.2 Some patients have reported erythema, swelling, and pain at the injection site that subsided after switching from a sesame oil formulation to one with cottonseed oil. In one trial, the six-month mean systolic blood pressure increased (114.5 vs. 119.5mmHg, p=0.041) but this increase was not found to have clinical significance. Depression and suicidality have been reported with testosterone use, but it was not reported in any of the studies above. Surveys given to patients switching from IM to SC showed that the vast majority of subjects preferred SC.4

On the Horizon
The 2015 Subcutaneous Testosterone Enanthate Safety in Adult Men Diagnosed with Hypogonadism (STEADY™) trial was presented at the Endocrine Society Annual Meeting in April 2017 and American Urology Association Annual Meeting in May 2017. Antares Pharma claims the results of this trial (which are not yet published) demonstrated Xyosted®, formerly called QuickShot Testosterone, achieved steady state testosterone levels.7 However, the FDA has declined to approve Antares Pharma’s new drug application for Xyosted® based on two safety concerns: risk of increased blood pressure and occurrence of depression and suicidality.8 The FDA’s response letter did not cite any manufacturing, device, or efficacy issues. The company plans to meet with the FDA to discuss a path to the approval of Xyosted®.

Conclusion
When injected at weekly intervals, SC testosterone appears to be a safe and effective alternative to IM injection. Overall, weekly SC testosterone offers stable total testosterone levels with infrequent supraphysiologic peaks or subtherapeutic troughs. In transgender men, SC testosterone results in appropriate masculinization. In cisgender men, it alleviates symptoms of hypogonadism. BMI does not appear to affect the ability of SC testosterone to achieve appropriate serum levels. Weekly SC testosterone appears to have dose-proportional kinetics with an increase in dose resulting in a proportional increase in serum testosterone levels. Mild, transient injection site reactions appear to be the most frequently reported adverse reaction to SC testosterone. With the evidence supporting the use of SC testosterone and at least one pharmaceutical company already seeking approval for it, a testosterone suspension product approved for subcutaneous administration is likely to become available soon.

References:
1. Spratt DI, Stewart II, Savage C, et al. Subcutaneous injection of testosterone is an effective and preferred alternative to intramuscular injection: demonstration in female-to-male transgender patients. J Clin Endocrinol Metab. 2017;102(7):2349–55.
2. Kaminetsky J, Jaffe JS, Swerdloff RS. Pharmacokinetic profile of subcutaneous testosterone enanthate delivered via a novel, prefilled single-use autoinjector: a phase II study”. Sex Med. 2015;3:269–279.
3. McFarland J, Craig W, Clarke NJ, Spratt DI. Serum testosterone concentrations remain stable between injections in patients receiving subcutaneous testosterone. J Endo Soc. 2017;1(8):1095-1103.
4. Olson J, Schrager SM, Clark LF, Dunlap SL, Belzer M. Subcutaneous testosterone: an effective delivery mechanism for masculinizing young transgender men. LGBT Health. 2014;1(3)165–7.
5. Al-Futaisi AM, Al-Zakwani IS, Almahrezi AM, Morris D. Subcutaneous administration of testosterone: a pilot study report. Saudi Med J. 2006;27(12):1843–6.
6. McMahon CG, Shusterman N, Cohen B. Pharmacokinetics, clinical efficacy, safety profile, and patient-reported outcomes in patients receiving subcutaneous testosterone pellets 900mg for treatment of symptoms associated with androgen deficiency. J Sex Med. 2017;14:883–90.
7. “Antares Pharma Announces Poster Presentation of Quickshot Testosterone Data at the Endocrine Society Annual Meeting”. https://globenewswire.com/news-release/2017/04/03/953464/0/en/Antares-Pharma-Announces-Poster-Presentation-of-Quickshot-Testosterone-Data-at-the-Endocrine-Society-Annual-Meeting.html. 03 Apr. 2017. Accessed November 8, 2017.
8. “Antares Pharma Receives Complete Response Letter from the FDA for XYOSTED™”. https://seekingalpha.com/article/4115409-update-antares-pharma-post-complete-response-letter. 20 Oct. 2017. Accessed November 8, 2017.

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